chr15-63044030-G-C

Position:

• chr15-63044030-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The ENST00000403994.9(TPM1):​c.118G>C​(p.Glu40Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E40K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM1 ENST00000403994.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

Genes affected

TPM1 (HGNC:12010): (tropomyosin 1) This gene is a member of the tropomyosin family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosin is composed of two alpha-helical chains arranged as a coiled-coil. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. The encoded protein is one type of alpha helical chain that forms the predominant tropomyosin of striated muscle, where it also functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. In smooth muscle and non-muscle cells, alternatively spliced transcript variants encoding a range of isoforms have been described. Mutations in this gene are associated with type 3 familial hypertrophic cardiomyopathy and dilated cardiomyopathy 1Y. [provided by RefSeq, Jun 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a coiled_coil_region (size 283) in uniprot entity TPM1_HUMAN there are 129 pathogenic changes around while only 5 benign (96%) in ENST00000403994.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-63044030-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TPM1. . Gene score misZ 2.8677 (greater than the threshold 3.09). Trascript score misZ 3.9402 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, left ventricular noncompaction, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 3, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1Y.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.118G>C	p.Glu40Gln	missense_variant	2/10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.118G>C	p.Glu40Gln	missense_variant	2/10	1	NM_001018005.2	ENSP00000385107	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 04, 2017

A variant of uncertain significance has been identified in the TPM1 gene. The E40Q variant has not been published as pathogenic or been reported as benign to our knowledge. Additionally, this variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E40Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, a likely pathogenic missense variant at the same residue (E40K) has been previously reported in association with DCM (Olson et al., 2001), supporting the functional importance of this residue. Nevertheless, the E40Q variant has not been observed in a significant number of affected individuals and it lacks both segregation and functional studies which would further clarify its pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
CardioboostCm	Uncertain	0.84
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	.;.;D;.;D;T;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H;H;.;.;H;.;H;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D
PROVEAN	Benign	-1.7	N;N;.;D;N;N;N;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D;D;.;D;D;D;D;.
Sift4G	Uncertain	0.031	D;D;D;D;D;T;D;.
Polyphen		0.92, 0.92	.;.;.;.;P;P;.;.
Vest4		0.65
MutPred		0.12		.;.;.;.;.;Loss of phosphorylation at S87 (P = 0.1531);.;.;
MVP		0.94
MPC		2.1
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104894501; hg19: chr15-63336229;